BACKGROUND Syphilis continues to be a major global health threat with 11 million new infections each year, and a global burden of 36 million cases. The causative agent of syphilis, Treponema pallidum subspecies pallidum, is a highly virulent bacterium, however the molecular mechanisms underlying T. pallidum pathogenesis remain to be definitively identified. This is due to the fact that T. pallidum is currently uncultivatable, inherently fragile and thus difficult to work with, and phylogenetically distinct with no conventional virulence factor homologs found in other pathogens. In fact, approximately 30% of its predicted protein-coding genes have no known orthologs or assigned functions. Here we employed a structural bioinformatics approach using Phyre2-based tertiary structure modeling to improve our understanding of T. pallidum protein function on a proteome-wide scale. RESULTS Phyre2-based tertiary structure modeling generated high-confidence predictions for 80% of the T. pallidum proteome (780/978 predicted proteins). Tertiary structure modeling also inferred the same function as primary structure-based annotations from genome sequencing pipelines for 525/605 proteins (87%), which represents 54% (525/978) of all T. pallidum proteins. Of the 175 T. pallidum proteins modeled with high confidence that were not assigned functions in the previously annotated published proteome, 167 (95%) were able to be assigned predicted functions. Twenty-one of the 175 hypothetical proteins modeled with high confidence were also predicted to exhibit significant structural similarity with proteins experimentally confirmed to be required for virulence in other pathogens. CONCLUSIONS Phyre2-based structural modeling is a powerful bioinformatics tool that has provided insight into the potential structure and function of the majority of T. pallidum proteins and helped validate the primary structure-based annotation of more than 50% of all T. pallidum proteins with high confidence. This work represents the first T. pallidum proteome-wide structural modeling study and is one of few studies to apply this approach for the functional annotation of a whole proteome.

中文翻译：

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梅毒螺旋体亚种苍白螺旋体亚种的蛋白质组范围内的结构建模对功能的洞察力。

背景技术梅毒仍然是全球主要的健康威胁，每年有1100万新感染，全球负担3600万病例。梅毒的致病菌，梅毒螺旋体亚种苍白球菌，是一种高毒力细菌，然而，关于梅毒螺旋体发病机理的分子机制仍有待确定。这是由于以下事实：苍白螺旋体目前无法耕种，天生易碎，因此难以使用，并且在系统发育上也与众不同，在其他病原体中均未发现常规毒力因子同源物。实际上，其大约30％的预测蛋白质编码基因没有已知的直系同源物或指定功能。在这里，我们采用了基于Phyre2的三级结构建模的结构生物信息学方法，以提高对T的理解。苍白球蛋白功能在蛋白质组范围内。结果基于Phyre2的三级结构建模对80％的苍白螺旋体蛋白质组（780/978个预测蛋白）产生了高可信度预测。三重结构建模还从525/605蛋白（87％）的基因组测序管线中推断出与基于一级结构的注释相同的功能，占所有苍白螺旋体蛋白的54％（525/978）。在175种以高可信度建模的苍白螺旋体蛋白中，先前注释的已发表蛋白质组中未分配功能，其中167种（95％）能够分配预测功能。还预测了以高可信度建模的175种假设蛋白质中的21种与实验证实在其他病原体中需要毒力的蛋白质具有显着的结构相似性。结论基于Phyre2的结构建模是一种功能强大的生物信息学工具，它提供了对大多数苍白螺旋体蛋白质潜在结构和功能的洞察力，并帮助验证了超过50％的所有苍白螺旋体蛋白质基于一级结构的注释。高信心。这项工作代表了首个梅毒螺旋体全蛋白质组结构建模研究，并且是将这种方法用于整个蛋白质组功能注释的少数研究之一。